title: The zinc finger transcription factor RP58 negatively regulates Rnd2 for the control of neuronal migration during cerebral cortical development.
abstract: The zinc finger transcription factor RP58 (also known as ZNF238) regulates neurogenesis of the mouse neocortex and cerebellum (Okado et al. 2009; Xiang et al. 2011; Baubet et al. 2012; Ohtaka-Maruyama et al. 2013), but its mechanism of action remains unclear. In this study, we report a cell-autonomous function for RP58 during the differentiation of embryonic cortical projection neurons via its activities as a transcriptional repressor. Disruption of RP58 expression alters the differentiation of immature neurons and impairs their migration and positioning within the mouse cerebral cortex. Loss of RP58 within the embryonic cortex also leads to elevated mRNA for Rnd2, a member of the Rnd family of atypical RhoA-like GTPase proteins important for cortical neuron migration (Heng et al. 2008). Mechanistically, RP58 represses transcription of Rnd2 via binding to a 3'-regulatory enhancer in a sequence-specific fashion. Using reporter assays, we found that RP58 repression of Rnd2 is competed by proneural basic helix-loop-helix transcriptional activators. Finally, our rescue experiments revealed that negative regulation of Rnd2 by RP58 was important for cortical cell migration in vivo. Taken together, these studies demonstrate that RP58 is a key player in the transcriptional control of cell migration in the developing cerebral cortex.
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Florey Institute of Neuroscience and Mental Health, Genetics Lane, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia.
authors.forename: Julian Ik-Tsen
authors.initials: JI
authors.lastname: Heng
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia Florey Institute of Neuroscience and Mental Health, Genetics Lane, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Ohtaka-Maruyama
authors.affiliation: Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Okado
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan and.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kasai
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Diogo
authors.initials: D
authors.lastname: Castro
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Genetics Lane, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia.
authors.forename: Seong-Seng
authors.initials: SS
authors.lastname: Tan
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C520669:Zbtb18 protein, mouse; C475019:Rnd2 protein, mouse; D020741:rho GTP-Binding Proteins
keywords: cerebral cortex; migration; pattern formation; transcription factor